Synthesis of enantiopure Δ2-isoxazoline derivatives and evaluation of their affinity and efficacy profiles at human β-adrenergic receptor subtypes

The new enantiomerically pure 3-substituted-Δ2-isoxazolin-5-yl-ethanolamines (+)-6a/(−)-6b, (−)-6a/(+)-6b, and (+)-7a/(−)-7b, prepared via a 1,3-dipolar cycloaddition-based approach, were tested for their affinity at human β1-, β2-, and β3-adrenergic receptor (β-AR) subtypes stably expressed in CHO cells. The corresponding 3-isopropenyl derivatives (+)-5a/(−)-5b, (−)-5a/(+)-5b, and some isoxazole analogs were also tested. The binding affinities at the β-ARs of the isoxazolinyl amino alcohols were significantly lower than those of the corresponding isoxazole derivatives. A stereochemical effect was observed, since the process of molecular recognition is predominantly controlled by the (S)-configuration of the stereogenic center located at the 5 position of the heterocycle rather than by that of the stereocenter carrying the secondary alcohol group. On the contrary, the stereochemical features marginally affected the efficacy response; as a matter of fact, functional tests carried out on Δ2-isoxazoline derivatives provided with a detectable binding affinity showed the overall profile of neutral antagonists at all three β-AR subtypes.

A group of enantiomerically pure 3-substituted-Δ2-isoxazolin-5-yl-ethanolamines was prepared and tested for their affinity and efficacy at human β1-, β2-, and β3-adrenergic receptor subtypes.Figure optionsDownload as PowerPoint slide